Chemically modified ion mobility separation apparatus and method

ABSTRACT

An ion mobility spectrometry apparatus and method used to separate ions and select some of the ions using an AC gate; the selected ions are further separated along a drift axis of a drift tube, where the AC gate is controlled using a series of AC voltages and/or frequencies to select different ions for the drift tube.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 16/396,715, filed on Apr. 28, 2019, which is a continuation ofU.S. patent application Ser. No. 15/665,421, filed on Jul. 31, 2017 andnow issued as U.S. Pat. No. 10,276,358. Application Ser. No. 15/665,421is a continuation-in-part of U.S. patent application Ser. No. 14992053,filed on Jan. 11, 2016, which is a continuation of application Ser. No.14214558, filed on Mar. 14, 2014, which claims the benefit of andpriority to corresponding U.S. Provisional Patent Application Numbers61784324, filed on Mar. 14, 2013 and 61801722, filed on Mar. 15, 2013,and which is a continuation-in-part of U.S. patent application Ser. No.12763092, filed on Apr. 19, 2010 and now issued as U.S. Pat. No.9,177,770; the entire content of these applications are hereinincorporated by reference.

Application Ser. No. 15/665,421 is also a continuation-in-part of U.S.patent application Ser. No. 14/537,863, filed on Nov. 10, 2014, which isa continuation of U.S. patent application Ser. No. 13/475,993, filed May20, 2012. Application Ser. No. 13/475,993 is a continuation-in-part ofU.S. patent application Ser. No. 13/360,758, filed Jan. 29, 2012 and nowissued as U.S. Pat. No. 8,492,712, which is a division of applicationSer. No. 12/471,101, filed May 22, 2009, the latter now issued as U.S.Pat. No. 8,106,352, which is a continuation of U.S. patent applicationSer. No. 11/618,430, filed Dec. 29, 2006, the latter now issued as U.S.Pat. No. 7,576,321, which claims priority from Provisional Application60/766,226, filed Jan. 2, 2006. Application Ser. No. 13/475,993 is acontinuation-in-part of U.S. patent application Ser. No. 13/360,760,filed Jan. 29, 2012, which is a division of application Ser. No.12/471,101, filed May 22, 2009, the latter now issued as U.S. Pat. No.8,106,352, which is a continuation of U.S. patent application Ser. No.11/618,430, filed Dec. 29, 2006, the latter now issued as U.S. Pat. No.7,576,321, which claims priority from Provisional Application60/766,226, filed Jan. 2, 2006. Application Ser. No. 13/475,993 is acontinuation-in-part of U.S. patent application Ser. No. 12/695,111,filed Jan. 27, 2010. Application Ser. No. 13/475,993 is acontinuation-in-part of U.S. patent application Ser. No. 12/577,062,filed Oct. 9, 2009, which claims priority from Provisional Application61/104,319, filed Oct. 10, 2008. Application Ser. No. 13/475,993 is acontinuation-in-part of U.S. patent application Ser. No. 11/776,392,filed Jul. 11, 2007, which claims priority from Provisional Application60/891,532, filed Feb. 26, 2007 and claims priority from ProvisionalApplication 60/807,031, filed Jul. 11, 2006. Application Ser. No.13/475,993 also claims the benefit of and priority to corresponding U.S.Provisional Patent Application No. 61/488,438, filed May 20, 2011. Theentire contents of all of the above applications are incorporated hereinby reference in their entirety.

BACKGROUND OF THE INVENTION

Many analytical instruments, such as ion mobility spectrometers (IMS),can require a gating device for turning on and off a flowing stream ofions and/or other charged particles. IMS are widely used in fieldchemical analysis. IMS separate ionic species based on their ionmobility in a given media (either gas or liquid). Recent development ofthe IMS technology results in two forms of IMS instruments and systems.The time-of-flight (TOF) IMS separate ions based on their steady stateion mobilities under constant electric field. High resolving power withIMS has been achieved with the TOF-IMS instruments. Alternatively,devices that separate ions based their mobility changes under high fieldconditions, such as field asymmetric ion mobility spectrometer (FAIMS)or differential mobility spectrometer (DMS), can also be used.

Even though the gating device is a minor component in the overall designof an IMS, if manufactured correctly, this component can improve the IMSresolution and system performance. The gating device is used to regulatethe injection of ion packets into the analytical instrument. There aremany deficiencies with the current approaches for manufacturing gatingdevices.

Traditionally the gating device has been used to regulate the injectionof ion packets into the analytical instrument. Even though the gatingdevice is a minor component in the overall design of an IMS, this deviceis an important part that can improve the level resolution between peaksin the IMS by providing a compact ion packet without significantdiffusion. Many inventions have been proposed around the manufacturingand designing the gating device for improving the resolution withoutmajor improvements. The present invention modifies the gating device ina manner that improves peak resolution and is able to control which sizeions are injected into the analytical instrument. This novel gatingdevice significantly reduces the analysis of complex samples withmultiple components such that lower mobility ions are not able to enterthe drift tube.

Since it was invented in the early 1970's, ion mobility spectrometry(IMS) has been developed into a powerful analytical tool used in avariety of applications. There are three major forms of this instrumentincluding independent chemical detection systems, chromatographicdetectors, or hyphenated IMS mass spectrometry (MS) systems. As anindependent detection system, IMS qualitatively and quantitativelydetects substances in different forms relying on its capability toionize the target substance, to separate the target substance frombackground based on interactions with a drift gas (i.e. a carrier gas),and to detect the substance in its ionized form. As a chromatographicdetector, IMS acquires multiple ion mobility spectra ofchromatographically separated substances. In combined IMS-MS systems,IMS is used as a separation method to isolate target substances beforemass analysis. However, the resolution of IMS is generally consider low,often regulating such devices to qualitative use or use in environmentswith low levels of interferants with respect to the substances ofinterest.

The basic common components of an IMS system consist of an ionizationsource, a drift tube that includes a reaction region, an ion shuttergrid, a drift region, and an ion detector. In gas phase analysis thesample to be analyzed is introduced into the reaction region by an inertcarrier gas, ionization of the sample is often completed by passing thesample through a reaction region and/or a radioactive 63Ni source. Theions that are formed are directed toward the drift region by an electricfield applied to drift rings that establish the drift region, and anarrow pulse of ions is then injected into, and/or allowed to enter, thedrift region via an ion shutter grid. Once in the drift region, ions ofthe sample are separated based upon their ion mobilities and theirarrival time at a detector is an indication of ion mobility which can berelated to ion mass. However, it is to be understood that ion mobilityis not only related to ion mass, but rather is fundamentally related tothe ion-drift gas interaction potential which is not solely dependent onion mass.

Ion mobility spectrometers (IMS) have become a common tool for detectingtrace amounts of chemical and/or biological molecules. Compared to otherspectrometric chemical analysis technologies, e.g., mass spectrometry,IMS is a relatively low resolution technique. The IMS advantages of veryhigh sensitivity, small size, low power consumption, and ambientpressure operation are in some cases completely offset, or at a minimum,reduced by the lack of sufficient resolution to prevent unwantedresponses to interfering chemical and/or biological molecules. The falsepositives that result can range from minor nuisances in some scenariosto major headaches in others. Interfering chemical and/or biologicalmolecules can have very similar ion mobilities which in turn cansignificantly limit detecting and identifying low levels of the targetedchemical and/or biological molecules in the sample.

The present state of the art ion mobility spectrometers lack the abilityto directly reduce the occurrence of interfering chemical and/orbiological molecules in a sample's analysis. It is the purpose of thisinvention to overcome these obstacles by making the use of across-directional gas flow in a drift tube and/or using a segmenteddrift tube for pre-separation.

SUMMARY OF THE INVENTION

The present invention generally relates to systems and methods fortransmitting beams of charged particles, and in particular to suchsystems and methods that employ defecting at least one set of gridelements into the same plane, such that the grid elements areinterleaved.

In one embodiment of the present invention, at least one electricallysubstrate (conducting or non-conducting) is used to deflect at least oneset of the grid elements into the same plane, such that the gridelements are interleaved. The ion gate has a first and second set ofelectrically isolated grid elements that lie in the same plane where therespective sets of grid elements are applied to alternate potentials.The advanced grid manufacturing methods and features are disclosed.

The present invention generally relates to systems and methods fortransmitting beams of charged particles, and in particular to suchsystems and methods that let only a portion of ions to the drift tube ofthe IMS by employing an AC voltage (generated by one or more AC powersupplies) on the gate wires. By using an AC voltage there is a reductionin the size of the ion depletion area in front of the gate when it isclosed, thereby providing a higher peak resolution. In addition the ACgate can be used to separate ions.

The present invention relates to a cross-directional drift tube designfor an ion mobility spectrometer wherein the drift gas flow is in adirection that is substantially neither parallel nor antiparallel to thedrift axis of ions. A cross-directional drift tube with one or moredrift segments allows rapid drift tube clean up and flexible drift mediacontrol. A segmented drift tube is used for pre-separation of complexsample before separating samples in the subsequent drift segments. Thecross flow design and segmented drift tube can also be used together forenhanced separation performance. In another aspect of the presentinvention, at least one chemical modifier is added to the drift gas in across-directional gas flow that interacts selectively with at least onecomponent of the sample in a drift tube. The component may be impuritiesand/or interferences in the sample whereby the chemical modifierenhances sample resolution by shifting the components drift times. Thechemical modifier interaction forces may include hydrogen bonding,dipole-dipole, and steric hindering effects, but are not limited to onlythese.

The present invention also relates to various aspects ofMulti-Dimensional Ion Mobility Spectrometry (MDIMS) methods andapparatus. In various embodiments, the MDIMS of the present inventionsdifferentiate themselves from conventional ion mobility spectrometry(IMS) by innovatively integrating multiple ion mobility based separationsteps in one device. In various embodiments, the present inventionprovides higher resolution and higher sensitivity than conventional IMSdevices and operational approaches. Various embodiments of the presentinvention provide an integrated multiple dimensional time-of-flight ionmobility spectrometric system that ionizes, separates, and detectschemical species based on their ion mobilities. These systems generallyinclude: (a) at least one ionization source, (b) at least two driftregions, and (c) at least one ion detection device. In variousembodiments, these systems separate ions in one drift dimension underone set of drift conditions; and subsequently, the separated ions areintroduced into a higher dimension for further separation under the sameor a different set of drift conditions. In various embodiments, theseparation process can be repeated for one or more additional driftdimensions. Also, in various embodiments, the first drift dimension isused as one or more of an ionization source, reaction region ordesolvation region, and drift region for the system. For example, invarious embodiments, the electric field in the first drift dimension(first drift tube) can be used as a desolvation region for chargeddroplets.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other aspects, embodiments, and features of theinventions can be more fully understood from the following descriptionin conjunction with the accompanying drawings. In the drawings likereference characters generally refer to like features and structuralelements throughout the various figures. The drawings are notnecessarily to scale, emphasis instead being placed upon illustratingthe principles of the inventions.

FIG. 1 shows the completed ion gate from a front view.

FIG. 2 shows a cross-sectional top view of the ion gate.

FIGS. 3A and 3B show two different methods to deflect the grid elements.

FIG. 4 shows an alternative method to deflect the grid elements.

FIGS. 5A-5C illustrates the respective sets of gate elements.

FIG. 6 illustrates the process of manufacturing the ion gate.

FIG. 7A-7C shows the photo etched edges of the grid elements.

FIG. 8 schematically shows a construction of a Bradbury-Nielsen ion gateusing metalized dielectric rings and parallel wires.

FIG. 9 is a schematic example of a segmented Bradbury-Nielson gate.

FIG. 10 illustrates an operation method of an ion gate.

FIG. 11 shows an example of a gate using DC voltage.

FIG. 12 shows an example of a gate using AC voltage.

FIG. 13 shows the AC gate in the closed position and then completelyopen and then closed again.

FIG. 14 shows an example of an IMS spectrum using 20 parts per million(ppm) of an L-Tryptophan sample in 80/20 methanol and water using a DCvoltage on the ion gate.

FIG. 15 shows an example of an IMS spectrum using 20 parts per million(ppm) of an L-Tryptophan sample in 80/20 methanol and water using a ACvoltage on the ion gate.

FIG. 16 shows the AC mobility selecting gate in the closed positionhaving a voltage of 240 and then partially open having a voltage of 100and then closed again having a voltage of 240.

FIG. 17 shows the trajectory of ions using a 67 kHz AC frequency.

FIG. 18 shows gate wires that have a large surface area.

FIG. 19 shows 2 sets of gate wires aligned in phase.

FIG. 20 shows 4 sets of gate wires in an array that are out of phase.

FIG. 21 shows a typical asymmetric waveform used for differential ionmobility spectrometer or field asymmetric ion mobility spectrometer.

FIG. 22 shows an IMS using a cross-flow drift medium design.

FIG. 23 shows an IMS using a segmented drift tube for pre-separation.

FIG. 24 shows an IMS using a cross-flow drift medium design combinedwith a segmented drift tube.

FIG. 25 shows an IMS using a segmented drift tube design with cross flowfor adding specific modifiers to each segmented region.

FIG. 26 shows an IMS using a drift tube design with cross flow and withan AC gate.

DETAILED DESCRIPTION OF VARIOUS EMBODIMENTS

The terms ion mobility separator, ion mobility spectrometer, and ionmobility based spectrometer are used interchangeably in this invention,often referred to as IMS, including time-of-flight (TOF) IMS,differential mobility spectrometers (DMS), field asymmetric ion mobilityspectrometers (FAIMS) and their derived forms. A time of flight ionmobility spectrometer and its derived forms refers to, in its broadestsense, any ion mobility based separation device that characterizes ionsbased on their time of flight over a defined distance. A FAIMS, a DMS,and their derived forms separate ions based on their ion mobilitycharacteristics under high values of normalized electric field.

The systems and methods of the present inventions may make use of “drifttubes.” The term “drift tube” is used herein in accordance with theaccepted meaning of that term in the field of ion mobility spectrometry.A drift tube is a structure containing a neutral gas through which ionsare moved under the influence of an electrical field. It is to beunderstood that a “drift tube” does not need to be in the form of a tubeor cylinder. As understood in the art, a “drift tube” is not limited tothe circular or elliptical cross-sections found in a cylinder, but canhave any cross-sectional shape including, but not limited to, square,rectangular, circular, elliptical, semi-circular, triangular, etc. Inmany cases, a drift tube also refers to the ion transportation and/orion filter section of a FAIMS or DMS device.

Neutral gas is often referred to as a carrier gas, drift gas, buffergas, etc. and these terms are considered interchangeable herein. The gasis at a pressure such that the mean free path of the ion, or ions, ofinterest is less than the dimensions of the drift tube. That is, the gaspressure is chosen for viscous flow. Under conditions of viscous flow ofa gas in a channel, conditions are such that the mean free path is verysmall compared with the transverse dimensions of the channel. At thesepressures the flow characteristics are determined mainly by collisionsbetween the gas molecules, i.e. the viscosity of the gas. The flow maybe laminar or turbulent. It is preferred that the pressure in the drifttube is high enough that ions will travel a negligible distance,relative to the longitudinal length of the drift tube, therefore asteady-state ion mobility is achieved.

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases.

Unless otherwise specified in this document the term “particle” isintended to mean chemical and/or biological single or plurality ofsub-atomic particle, atom, molecule, large or macro molecule,nanoparticle, or other matters that are vapor, droplets, aerosol,liquid, solid that follow a mobile medium, where the medium can be agas, a liquid, supercritical fluid and/or other fluidic materials.

The present invention generally relates to systems and methods fortransmitting beams of charged particles, and in particular to suchsystems and methods that employ defecting at least one set of gridelements into the same plane.

As used herein, the term “grid element” generally refers to wire, rod,cable, thin metal foil piece that can be planar, square, rectangular,circular, elliptical, semi-circular, triangular, but not limited tothese examples. The grid element can be made of any electricallyconducting material.

The term “gate element” generally refers to a structure that includesone or more grid elements that can be spatially arranged with a gapbetween each other.

The axis of the drift tube along which ions move under the influence ofthe electrical drift field is referred to herein as a drift axis. Thedrift axis is often, but not necessarily, a longitudinal axis of thedrift tube.

As used herein, the term “analytical instrument” generally refers to ionmobility based spectrometer, MS, and any other instruments that have thesame or similar functions. Unless otherwise specified in this documentthe term “mass spectrometer” or MS is intended to mean any device orinstrument that measures the mass to charge ratio of achemical/biological compounds that have been converted to an ion orstores ions with the intention to determine the mass to charge ratio ata later time. Examples of MS include, but are not limited to: an iontrap mass spectrometer (ITMS), a time of flight mass spectrometer(TOFMS), and MS with one or more quadrupole mass filters.

One aspect of the invention relates to manufacturing an ion gate in sucha way that the ion gate can be produced in a simple, reproducible, andreliable manner. FIG. 6 illustrates a non-limiting process formanufacturing the ion gate. This method for manufacturing an ion gatefor a charged particle stream begins with the fabrication of the gateelements 603 and 607 that includes the grid elements. Each of the gateelements 603 and 607 are made so that the two different pairs of gridelements can be interleaved without contacting each other. Followed byassembling an insulating layer (electrically non-conductive, theinsulating layer can be any size and shape, such as a square or a diskwith openings, or a washer, that allows a different potential to thegate elements) 605 between the gate elements 603 and 607 to electricallyisolate the gate elements. The substrate throughout this patent istypically non-conducting, but can also be a conducting material for someapplications. Then two electrically non-conductive substrates 601 and609 are added to deflect the grid elements in the gate elements into thesame plane. FIG. 6 shows a non-limiting example, wherein twoelectrically non-conductive substrates are used. Similarly, oneelectrically non-conductive substrate can also be used to manufacturethe ion gate. Finally, the gate elements are secured together along withthe electrically non-conductive substrates and the insulating layer. Inan alternative embodiment, the gate elements can be segmented, thus eachsegment of the grid elements can be operated independently, i.e. openand close at different timing, as a segmented ion gate. The method formanufacturing an ion gate for a charged particle stream, can comprise ofelectrically isolated grid elements that lie in the same plane. Therespective sets of grid elements can be applied to alternate potentialsto close the gate and the same potential to open the gate. For example,the grid element is at 100 volts above and 100 volts below the referencepotential. The reference potential is the potential at the particularlocation of the gate in the drift tube. The steps used to manufacturethe ion gate can be in any order and comprise: fabricating at least twogate elements, wherein each gate element includes at least one set ofgrid elements; assembling an insulating layer between the gate elements;deflecting at least one set of grid elements into the same plane of theother set of grid elements with at least one substrate; and securing thegate elements and the non-conductive substrates together.

A non-limiting example of the completed ion gate is shown in FIG. 1. Theshape of the ion gate can be: square (shown), oval, circle, semicircle,triangle, rectangle, polygon, octagon, but not limited to theseexamples. FIG. 1 shows a front view of the completed ion gate. The iongate includes gate elements that contain the grid elements 103 are heldin place with several screws 105. The ion gate apparatus that is usedfor gating a charged particle stream comprises: at least two sets ofgrid elements that individual voltages can be applied to each set toopen and close; and at least one substrate for deflecting at least oneset of grid elements into the same plane of the other sets of gridelements. In addition an electrically insulating layer can be added toallow different voltages to be set to each set of grid elements.

Another aspect of the invention relates to providing an ion gate with aneffective gating function by applying a uniform tension on the gridelements, fabricating the gate elements such that the grid elements areequally spaced, and deflecting the grid elements into the same plane.

FIG. 2 shows a cross-sectional top view of the ion gate. Thecross-section shown in FIG. 2 is indicated in FIG. 1 with a cutting line107. The ion gate comprises a first and second electrically isolatedgate elements 204 and 206 that each have at least one grid element 205and 207. The electrically non-conductive or conductive substrate 208deflects the grid element 207 which is part of the gate element 206 intothe same plane as the deflected grid element 205 which is part of thegate element 204. The gate elements 204 and 206 are electricallyisolated by placing an insulating layer (electrically non-conductive orconductive) 210 between these gate elements. The grid elements aredeflected into the same plane 202 and are electrically isolated byinterleaving these sets of grid elements with a gap between each gridelement. FIG. 5C illustrates the respective sets of grid elements inFIG. 5A and FIG. 5B interleaved. In FIG. 2, the ion gate components aresecured together with a screw fastener 212. In this non-limitingexample, ether an electrically non-conducive material screw fastener maybe used or a conductive material fastener can be contained in anelectrically non-conductive standoff (not shown).

One embodiment of the present invention, involves using off-setelectrically non-conductive or conductive substrates to deflect the gridelements. FIG. 3A shows the electrically substrates 305 and 307 with nooff-set 301. FIG. 3B shows electrically substrates 305 and 307 with anoff-set 303. This off-set design may allow uniform deflection of gridelements and low cost manufacturing.

Another embodiment of the present invention, involves the shape of theelectrically non-conductive or conductive substrate to deflect the gridelements. The portion that deflects the grid element can be in the shapeof a wedge, hexagon, semi-circle, but not limited to these examples. Inaddition, the electrically non-conductive substrate portion thatdeflects the grid element can be independent to the secured electricallynon-conductive substrate. A non-limiting example is shown in FIG. 4,where a circular (not limited to only this shape) substrate 402 deflectsthe grid element and the secured substrate 404 holds the substrate 402in place.

Yet another embodiment of the present invention is the fabrication ofthe gate elements. The grid elements within the gate elements can beproduced by cutting, etching, evaporation or electroplating, but notlimited to these methods. In a non-limiting example, parallel rows ofgrid elements are formed by removing portions of a given thickness ofplanar metal foil by etching portions from the foil. This method forms aplurality of grid elements that are equally spaced. In addition toforming equally spaced grid elements within the gate element, the gridelements are made from the same gate element material as a singleentity. In this manner, the grid elements do not need to be fixed to thegate element through gluing (epoxy), glass soldering, or any otherattaching manner. Fabricating the gate elements by etching the gridelements is a robust and reproducible method for manufacturing the gridelements. In addition, since no gluing, soldering, or other attachingmanner is used in fabricating the gate elements, elevated temperaturesand/or thermal expansion of the grid elements are all uniform. The photochemical milling (etching) can be performed on one side or both sides ofthe material being etched.

FIG. 7A shows the shape (a pair of opposing concave fillets) of the gridelement etched on both sides of the material, etched from the top 701and the bottom 702 of the material. FIG. 7B shows the shape (a concavefillet) of the grid element etched on one side of the material, etchedfrom only the top side 704 of the material. The etched edge distance 703may be smaller or greater than the material thickness 705 depending onthe layout of the grid elements. For example, the etched edge distanceto the material thickness ratio is greater than zero, in particular1-50%, 50-100%, 100-500%. FIG. 7C shows three grid elements that areetched on both sides of the material. Photo chemical milling can produceuniform dimensions in grid element width 707 and gap 709 between gridelements forming a plurality of grid elements that are equally spaced.When the ion gate is a uniform product, injection of ion packets intothe drift tube are tight packets with limited background signal,therefore a higher signal to noise ratio can be achieved. In thisembodiment, regardless of manufacturing methods, the grid element is tobe made with a sharp edge, the geometry may generate a narrow gatingelectric field region resulting in high precision gating of chargeparticles. In an IMS device, a narrow ion pulse could be generated withprecision gate timing control. An ion gate apparatus for gating acharged particle stream comprises: at least two sets of electricallyinsulated grid elements on the same plane, the evenly spaced gridelements have at least one sharp edge face to adjacent grid element.

Another embodiment of the present invention is securing the gateelements together with non-conductive substrates and the insulatinglayer. The ion gate can be secured by clamping, soldering, screws, pins,but not limited to these examples. The insulating layer can be made fromany non-conductive material such as, ceramic, aluminum nitrate, but notlimited to these examples.

An alternative embodiment of manufacturing an “Tyndall” type of ion gatefor a charged particle stream involves two sets of electrically isolatedgrid elements, wherein the first set of grid elements is arranged withan offset in respect to the second set of the grid elements, such thatthe gaps of the first grid element is aligned with the second gridelements; each set of grid elements is applied to alternate potentialswhen the gate is closed and same potential when the gate is opened. Themethod involves the steps of: fabricating at least two gate elements byremoving portions of a substantially planar metal foil to form aplurality of grid elements; wherein each gate element includes at leastone set of grid elements; assembling an insulating layer between thegate elements; and securing the gate elements together.

In another embodiment of the invention, a metalized dielectric structureis used for the Bradbury-Nielsen gate. A ceramic material is coated withsingle or multiple layers of metallization materials. The metallizationprocess is commonly finished with a thin layer of nickel, gold or otherinert metal for enhanced chemical resistivity. FIG. 8 shows a uniqueconstruction method of a Bradbury-Nielsen ion gate using a metalizedceramic material. It is built with a frame ring, a tension ring 802 andparallel wires 805 that are pre-winded on a metal frame. One or therings, either the frame ring or the tension ring is metalized 815 with apattern 810 that connects every other wire to each other. In oneembodiment, the frame ring has metalized contacts 807 that are 1 mmapart (center to center). During the ion gate construction, the parallelwires are lined up with these contacts and form a firm contact while thetension ring is pushed down into the frame ring. As the wire is selectedto match the thermal expansion of the frame ring and tension ring, thewires can be maintained parallel while the IMS is operated underdifferent temperature conditions. The gate control voltage(s) areapplied to the wires by attaching an electrical lead to the contactpoint that is on the outside of the frame ring. Not only for metalizedceramic tube IMS design, the Bradbury-Nielsen ion gate can be used forother analytical instruments.

In various embodiments for symmetric IMS, an ion focusing method can beemployed to guide ions to a target collection area on the collector.Suitable focusing methods may include, but are not limited to, staticelectric field focusing and ion funnel focusing. An ion collector can besegmented to facilitate, collection of ions with specific ion mobility(drift time) or a certain range of mobilities on to different segment ofthe ion collectors. A segmented Bradbury-Nielson gate can be used toenhance the separation and collection.

In various embodiments of IMS instruments, wherein the Bradbury-Nielsongate can be segmented. A variety of geometries, including but notlimited to parallel, rectangular, concentric ring shape, can be used forthe segmentation, referring to FIG. 9, various embodiments can useparallel segmentation. Each segment of the ion gate, for example, 901,903, and 905, can be controlled to open at a different time. Such asegmented ion gate can be used as either first or second ion gate in atime-of-flight type ion mobility separator. While it is used as thesecond ion gate in a IMS, multiple portions of ions with different drifttime are allowed to pass through segmented ion gate, thus collected ondifferent sections of ion collectors, and recovered separately ifdesired.

In various embodiments, an apparatus of ion gate for an ion mobilityseparator comprising a segmented Bradbury-Nielson that contains multiplesections of Bradbury-Nielson gate. The segmented Bradbury-Nielson gatecan be used as a second gate in a time-of-flight type ion mobilityseparator. The segmented Bradbury-Nielson gate comprises a variety ofgeometries which may include but is not limited to: parallel,rectangular, concentric. The ion mobility separator further comprises asegmented ion collector where a plurality of sections of ion collectoris inline with the sections of the segmented Bradbury-Nielson gate.

This invention further describes a method and apparatus of ion gateoperation. In one embodiment, an AC voltage is used to close the gate.In a common operation of the Bradbury-Nielson gate, the ion gate is openwhen the adjacent grid elements are at the same potential and the iongate is closed when a DC voltage, e.g. 30V, 50V, 100V, 200V, or −30V,−50V, −100V, −200V are applied on the adjacent grid elements. Thevoltage creates an electric field that pushes ions toward the gridelement that is a lower potential, thus preventing ions from penetratingthrough the ion gate when closed.

During ion mobility measurements, the ion gate is opened for a shortperiod of time, e.g. 100 microseconds, and then closed for a period oftime, e.g. 20 millisecond, while ions are traveling in the drift tube.FIG. 10 illustrates a closed ion gate. When the applied voltage ishigher than the reference potential, a ‘+’ is shown for the gate wire(i.e. grid element) and when the applied voltage is lower than thereference potential, a ‘−’ is shown for the gate wire. The voltagedifference between the adjacent wires causes positive ions to becollected on the (−) wire and negative ions to be collected on the (+)wire. By repeating wire layout pattern of (+) and (−) wires, a largearea is covered and ions are prevented to pass through the ion gate. Inthis embodiment, an AC voltage instead of DC voltage is applied the gatewires. In this case, the potential of each wire is constantly changing.The potential on wire 1003 is ‘+’ and wire 1004 is ‘−’ at the state1001, and then the potential on wire 1003 is ‘−’ and wire 1004 is ‘+’ atthe state 1002. The state 1001 and 1002 repeats at certain frequency.The voltage and frequency of the AC applied to the adjacent wires isoptimized to completely close the ion gate. The ion gate is opened bysetting all gate wires at the same potential. The new gate configurationand operational method is not limited to be used for ion mobilityspectrometer, but can be used for any device that needs to shut off astream of charged particles.

In a variety of the embodiments, a method for operating an ion gate fora charged particle stream involves opening the ion gate by settingadjacent gate wires (grid elements) at the same potential; closing theion gate by setting adjacent gate wires at different potentials byapplying an AC voltage to the adjacent wires. The AC voltage can becontrolled to provide a given frequency and amplitude that that is mostsuitable for the intended operation. The frequency can be a constantand/or controlled to cover a broad range during a period when the iongate is closed. Similarly, the amplitude can be a constant and/orcontrolled in a range during a period of closing the gate. The ACvoltage may be a symmetric or asymmetric waveform (for example, awaveform is used for DMS and/or FAIMS, a typical example of the waveformis shown in FIG. 21). In a variety of operation modes, the AC poweredion gate can be operated as such, conducting a series of ion mobilitymeasurements under a series of different frequencies and/or amplitudes,and then integrating the series of ion mobility measurement data into anion mobility spectrum using common data processing algorithms, such assumming.

A Bradbury-Nielson gate is traditionally used for injecting short pulsesof ions into TOF mass spectrometers and ion mobility spectrometers toimprove the mass resolution of TOF instruments by reducing the initialpulse size as compared to other methods of ion injection. Therefore theprecise control of the ion pulse width admitted to the drift tube can becontrolled. However, the means for controlling the size of ions enteringthe drift tube using a Bradbury-Nielson gate has not been proposed todate.

One embodiment of the present invention is to use an AC voltage insteadof the commonly used DC voltage to control the amount of a ion pulsesgenerated and let through the gate. In a common operation of theBradbury-Nielson gate, the ion gate is open when the adjacent gridelements are at the same potential and the ion gate is closed when a DCvoltage, e.g. 30V, 50V, 100V, 200V, or −30V, −50V, −100V, −200V areapplied on the adjacent grid elements. The voltage creates an electricfield that pushes ions toward the grid element that is a lowerpotential, thus preventing ions from penetrating through the ion gatewhen closed. FIG. 11 shows an example of a gate using DC voltage.Negative sample ions 1101 travel toward the ion gate wires 1105 and 1006of the gate in a relatively straight line according the applied filed inthe reaction region (desolvation region) 1103 until they come close tothe gate wires where they are pulled toward the positive wires 1105 andare neutralized on the positive wires 1105 if the gate is not in theopen state. Since DC voltage is being used to control the gate, eachadjacent wire has a different polarity, either positive or negative.Therefore gate wires 1105 are positive and gate wires 1106 are negative.During ion mobility measurements the ion gate is opened for a shortperiod of time, e.g. 100 microseconds, and then closed for a period oftime, e.g. 20 millisecond, thereby letting a pulse of ions travel in thedrift tube 1108. During the closed state of the gate an ion depletionarea is formed 1110. The larger the area of the ion depletion area thelonger the gate needs to be opened to let ions through, since there is alow population of ions. In order to get higher resolution peaks in theIMS spectrum, a shorter opening period of time is preferred in order toget a narrow pulse of ions through with limited diffusion. By using anAC voltage instead of a DC voltage to close the gate the ion depletionarea can be reduced, in particular, by a half. The ion depletion areacan be reduced by an percentage by using an AC voltage.

In a variety of the embodiments, a method for operating an ion gate fora charged particle stream involves opening the ion gate by settingadjacent gate wires (grid elements) at the same potential; closing theion gate by setting adjacent gate wires at different potentials byapplying an AC voltage to the adjacent wires. The AC voltage can becontrolled to provide a given frequency and amplitude that that is mostsuitable for the intended operation. The frequency can be a constantand/or controlled to cover a broad range during a period when the iongate is partially open and/or closed. Similarly, the amplitude can be aconstant and/or controlled in a range during a period of closing thegate. The AC voltage may be a symmetric or asymmetric waveform. Thewaveform can be, but not limited to: sine, square, triangle, andsawtooth. In a variety of operation modes, the AC powered ion gate canbe operated as such, conducting a series of ion mobility measurementsunder a series of different frequencies and/or amplitudes, and thenintegrating the series of ion mobility measurement data into an ionmobility spectrum using common data processing algorithms, such assumming. FIG. 12 shows an example of a gate using AC voltage. Negativesample ions 1201 travel toward the ion gate wires 1205 of the gateaccording to the AC applied field until they come close to the gatewires where they are pulled toward the gate wires 1205 and areneutralized if the gate is not in the open state. Since AC voltage isbeing used to control the gate, each adjacent wire has a differentpolarity, which alternates between positive or negative. Therefore thegate wires 1205 are positive and are negative according to the appliedAC voltage. During ion mobility measurements, the ion gate is opened fora short period of time, e.g. 100 microseconds, and then closed for aperiod of time, e.g. 20 millisecond, while ions are traveling in thedrift tube 1208. During the closed state of the gate an ion depletionarea is formed 1210. By using an AC voltage instead of a DC voltage toclose the gate the ion depletion area is minimized, in particular, canbe reduced by a half thereby improving the operation of the ion gate.There is little or no space charge using the AC voltage as compared toDC voltage. Since the ion gate can create tighter ion pulses when it isopened the resolution of the peaks traveling through the drift tube 1208are significantly increased. FIG. 13 shows the AC gate in the closedposition 1301 and then completely open 1303 and then closed again 1305.The open 1303 position is for a shorter period of time than that whenusing a DC voltage.

Another embodiment of the present invention is to use an AC voltageinstead of DC voltage on an ion gate to filter ions according to theirsize and/or ion mobility. An apparatus and method is used to filter ionsaccording to their ion mobility by varying the AC potential on asegmented Bradbury-Nielson gate. Some of the components of the chargedparticle stream have a smaller size and/or shape (or ion mobility)compared to the other components of the charged particle stream. Thepresent invention controls the AC voltage on a segmentedBradbury-Nielson gate in order to filter small ions from larger ionsfrom an ionized sample before they enter the drift tube. FIG. 14 showsan example of an IMS spectrum using 20 parts per million (ppm) of anL-Tryptophan sample in 80/20 methanol and water using a DC voltage onthe ion gate. The reactant ion peak (RIP) and L-Tryptophan (L-Trp) areshown as peaks in the spectrum. When AC voltage is used on the ion gatesmaller sized ions such as the RIP peaks can be substantially eliminatedas shown in FIG. 15. The AC frequency can be tuned to control thespecific ion mobility that is excluded from being transmitted from theionized sample into the drift tube. For example, an AC frequency of 67kHz and a 100-240 voltage range between the gate wires would excludesmall ions having a 100 molecular weight size from the other ions in thesample that have a larger molecular weight greater than 100. FIG. 16shows the AC mobility selecting gate in the closed position 1601 havinga voltage of 240 and then partially open 1603 having a voltage of 100and then closed again 1605 having a voltage of 240. In this mode, whenthe gate is open 1603, only larger molecular weight (low ion mobility)components of the sample can get through the gate without gettingneutralized on the gate wires. The AC mobility selecting gate works bytuning the AC frequency in the reaction region (desolvation region) 1705as shown in FIG. 17. When components of a sample have different ionmobilities, sizes or molecular weights, the AC frequency has a strongeror weaker effect on the components travel. For example, for two negativeions where one 701 has a molecular weight of 100 and the other ion 1703has a molecular weight of 200 the trajectory using a 67 kHz frequency issubstantially different as shown in FIG. 17. The smaller (high mobility)ion 1701 has a larger oscillation 1708 than the larger (low mobility)ion's oscillation 1706. When the AC gate is only partially open as inFIG. 16 the larger ion 1703 passes the gate wires onto the drift tube1708 and the smaller ion 1701 is neutralized on the gate wire.

In yet another embodiment, the wires of the AC gate can be configured toenhance the size selection. As shown in FIG. 18, the wires 1815 can bemade rectangular such that certain small ions would have a largersurface area in the direction that is parallel to the charged particlestream to be neutralized on and the frequency tuning could beestablished such that the small and large ions are within a fewmolecular weight units and still be differentiated. Alternatively, thewires 1815 in FIG. 18 can be 2 or more that are aligned in phase asshown in FIG. 19 or 2 or more are out of phase in any array as shown inFIG. 20. When 2 or more wires are used in an array that are out of phasea specific component ion mobility can be filtered out thereby lettingthe other components through the gate. The configuration shown in FIG.20 provides the ability eliminate one specific sample component fromtraveling through the gate to the drift tube 2008. This is differentfrom other configurations where they operate as a cut-off whereby allsmall size and/or shape ions are eliminated at a certain point. In avariety of the embodiments, a method for operating an AC ion gate forcharged particles stream involves, applying an AC voltage to 2 or morewires; the AC voltage are out of phase, selectively eliminating one ormore sample components from the charged particle stream while partiallyopening the ion gate; conducting ion mobility and/or mass measurement.The operating method may further include applying a series of ACvoltages in certain sequence during ion mobility measurement. Suchsequence may include AC voltage that selectively eliminating samplecomponent ions in the charge particle stream from high ion mobility tolow ion mobility; or from low mobility to high mobility; or selectivelyfor one or more targeted sample components with certain ion mobilities.The frequency and/or amplitude of the AC voltages in such sequence maybe altered in a continuous or discrete fashion.

In a variety of the embodiments, a method for operating an AC ion gatefor a charged particle stream involves; applying an AC voltage to one ormore of the gate wires to partially open and/or close the ion gate,partially opening the ion gate with an AC voltage that is greater than 0but less than the AC voltage used to close the ion gate, and filtering apercentage of some components of the charged particle stream from theother components of the particle stream by neutralizing such componentson the ion gate wires. The frequency and/or amplitude of the AC voltagecan be controlled in a range or held constant during a period of closingthe gate. The AC voltage can be a symmetric or asymmetric waveform. Thepercentage of some components of the charged particle stream beingfiltered from the other components can be 0 to 100%, in particular,100%, greater than 75%, greater than 50%, greater than 25%, greater than10%, or a small percentage being greater than 0%.

In one embodiment, the method of operating an AC gate may include aseries of pulse of ions that allow different components of chargedparticle stream to pass through the AC gate; and analyze the componentsof charged particle stream based on their ion mobility and/or mass tocharge ratio.

In one preferred embodiment of a time of flight ion mobilityspectrometer include an ionization source located on one end of the ionmobility spectrometer is used to ionize the samples. An electric fieldis used to guide the ionized sample toward an ion gate. On the ion gate,at least one AC voltage is applied to the gate elements where at leastone pulse of the ionized sample is passed into a drift tube. The ionizedsample is then guided by another electric field to guide the pulse(s) ofions toward an ion detector. The ion detector is commonly located at theother end of the spectrometer. The AC voltage can be composed using oneor more waveform. The AC voltage has a waveform that is substantiallysame as the asymmetric waveform used in differential/field asymmetricion mobility spectrometers, an example of such waveform is shown in FIG.21. The time of flight ion mobility spectrometer can offer twoseparation mechanisms in one integrated structure. The ionized samplemixture is first filtered by the AC ion gate based on their ion mobilitydifferential under high electric field condition between grid elements;only selected ions under a given AC voltage condition can pass the iongate as a pulse of ions, and then, the pulse of ions are furtherseparated ion the drift tube of the time of flight ion mobilityspectrometer based on their low field ion mobility. The AC gate cansweep through a range of AC voltages to select ions with different highfield mobility to be pulsed into the drift tube for further separation.With this measurement, a 3D separation plot could be generated with oneaxis of low field ion mobility, or drift time, and another axis ofcompensation voltage of the asymmetric waveform for DMS/FAIMS, and thethird as axis of ion intensity.

Even though many embodiments and examples given in this disclosure referto ion gate for general IMS device, these devices can be operated underlow vacuum, ambient or high pressure conditions. Alternatively, the iongate can be operated in liquid for liquid phase IMS or other devices,such as electrophoretic devices, where packets of ions need to beformed. The ion gate can also be used under vacuum conditions forgenerating ion packets for mass spectrometers, such as a time of flightmass spectrometer. This invention discloses gating methods andapparatuses that can be used for any device where packets of chargedparticles need to be formed.

In various aspects, the present invention provides multi-dimensional ionmobility spectrometry (MDIMS) systems, preferably with multi-dimensionalelectric field designs in one integrated spectrometer, and methods ofoperating such systems. In various embodiments, the MDIMS systems and/ormethods provide improved sensitivity and resolution compared toconventional single dimension drift tubes. In various embodiments,improved sensitivity can be achieved by using the first dimension as anion storage region to improve system duty cycle. In various embodimentsthe MDIMS systems and/or methods provide improved mobility resolution.In various embodiments, improvements can be achieved by the use of driftregions which can further separate ions that are or have already beenseparated based on their mobilities. In various embodiments, as ionspecies are being separated in the first dimension, the columbicrepulsion among them is reduced by transferring them to a second IMSdimension (e.g., using a kickout pulse). Thus, in various embodiments,higher mobility resolution can be experienced in the second dimension.In various embodiments, the first dimension can be used as an ionreaction region where further ion conversion can be achieved. In variousembodiments of a MDIMS, and appropriate electric field application, aMDIMS can be used to detect both positive and negative ionssubstantially simultaneously.

In various embodiments of the MDIMS, it is understood that a preferredembodiment is to arrange the drift axis of each dimension in orthogonalgeometry, however, the drift axis can be arranged in parallel,anti-parallel or with an angle in between to achieve similar results.

It is to be understood, that the electrical drift field strength-to-gasnumber density ratio (E/N value, often expressed in units of Townsend)in all IMS dimensions of the present MDIMS apparatus and methods ischosen to establish a steady-state drift environment, sometimes referredto as a low field environment.

With the MDIMS of the present inventions, the ion mobility spectrum canbe represented, e.g., in a 2-D or 3-D plot, and can use a non-lineardetection window. Chemicals can be identified in their 1-D, 2-D or 3-Dmobility profile. This mobility profiling method can provide additionalinformation and thus, can provide greater confidence for chemical (e.g.,explosive) identification.

In various embodiments a Dual Polarity Ion Extraction (DPIE) operationalmode can be conducted using the first dimension as a flow through cellwhere both positive and negative ions are brought into the first driftchamber by gas flow while the drift voltage in the first dimension isturned off (i.e., substantially no drift field is present). At apredetermined time ions are and kicked out into the second dimension,preferably such that the positive and negative ions in the firstdimension are substantially simultaneously extracted into two separateddrift chambers in the second dimension. After ions are separated in thesecond dimension, they can be further separated and detected in thethird or higher dimensions.

In various embodiments, ionized samples are guided into and/or formed inthe first drift region and subject to a first order separation based onmobility (resembling conventional IMS). At a given predetermined time,separated ions in the first dimension (first drift tube) are kicked outinto the second drift dimension drift region where they are separated inthe direction that is substantially perpendicular to the first driftdirection. The same process can be continued in the higher dimensions ifdesired with further dimensions of IMS.

In one embodiment, the three walls in the first dimension are at 1,000 Vand the gate grids are set at 0 V and 2,000 V respectively. The samplegas flow used to carry ions through the first dimension can be exhaust,e.g., behind the first dimension detector. After ions are separated inthe second dimension, a kick out voltage can be applied to bring theseparated ions into the third dimension. In a continuous sampledetection scenario, the sequence will repeat. For a chemical mixturethat may form both positive and negative ions, various embodiments ofthe DPIE technique can extract more than 50% of both positive andnegative ions into the second dimension.

In various embodiments, the MDIMS devices can transport ions betweeneach dimension without significantly losing resolving power. In variousembodiments, when ions are separated in the first dimension; they canlook like a thin plate. To move them into the direction that isperpendicular to the first dimension, voltages are changed on theappropriate electrodes (typically an electrode opposite the inlet, theinlet itself, or both) within a microsecond range. The electric fieldduring these kick out moments can be manipulated to create temporaryhigh and low electric field zones. The thin plate in the high field zonecan be compressed into a thin line in the low field zone of the seconddimension.

In various embodiments, a MDIMS comprises an ionization source to, forexample, (a) generate reactant ions and a reaction region where reactantions can react with samples and form product ions to be detected forsample identification; (b) generate sample ions for detection, (c) orboth. The reaction region can be guarded by ion guides that generate asubstantially continuous electric field to, e.g., lead the ions to thefirst dimension drift region (first drift tube).

In Multiple Step Separation (MSS) mode operation, a pulse of ions aregenerated by opening an ion gate, to introduce them into the firstdimension drift region; the ions are separated based on their mobilitiesunder the guidance a substantially continuous electric drift field inthe first drift tube. In one embodiment, the electric field is generatedby a series of ion guides. Each ion guide can comprise one or moreelectrodes; and different voltages can be applied on each electrode toestablish the potential difference across the first drift tube. Forexample, four electrodes can be used for each of the first dimension ionguides.

In various embodiments of MSS mode operation, as a first group of ionsreaches the first dimension detector matrix, a kick out voltage can beapplied to generate a high electric field that is perpendicular to thefirst dimension drift field, thus the ions separated in the firstdimension are moved into the second dimension drift region. An electricfield separator screen can be used to help define the electric field inthe second dimension. Ions introduced into the second field willcontinue to drift across the second dimension drift region and furtherseparation can be achieved. The ion guides in the second dimension canbe arranged similarly to the first dimension ion guides, for example, ifa third dimension of separation is desired. If a third dimension isdesired, complete square electrodes can be used as the ion guides. Ionsseparated in the second dimension can be detected by the detector. Thedetector can comprise multiple detectors according to required specialresolution of the spectrometer or a single detector.

In various embodiments, a partial kick out operation can be performedwhen ions are introduced from the first dimension to the seconddimension. If only a portion of the ions are kicked out, the mobilitymeasurement in the first dimension can be resumed after the kick out.Thus, an ion mobility spectrum can also be acquired independently in thefirst dimension. As a complete kick out can increase the sensitivity inthe second dimension, alternating between these operation methods can bebeneficial. In addition, a clean up operation, e.g., remove all ions inthe drift chambers by an applied “kick out” electric field for anextended period of time, can also be added between detection cycles.

The low dimension operation of the spectrometer can be used as fastscreening method to generate a quick survey of the ionic species fromthe ionization source. In combination with the normal operation of theMSS mode, the survey of the ionic species can be used as an index toguide upper dimension operations. The survey mode operation can also beused to selectively kick out ions of interest, simplifying higherdimension spectra, and saving total analysis.

Different drift/separation conditions can be established independentlyfor each dimension, e.g., different drift gases may be used in eachdimension or different drift gas temperatures in each dimension.

The MDIMS can be operated in a fashion where a number of multipledimensional positive ion mobility data is collected followed by a numberof multiple dimensional negative ion mobility data. The sequence can berealized, e.g., by alternation the polarities of electric fields in thespectrometer.

During MSS mode operation, the directions of the drift gas flow can beset to be counter to or across from the ion movement. The size of eachgas port can be selected depending on the flow required to achieve theflow pattern inside the spectrometer and preferably the drift flowsweeps the entire drift region and removes excessive sample moleculesand any other reactive neutral molecules.

One aspect of the present invention is a method and apparatus for usinga cross flow IMS apparatus for effectively removing neutral moleculesfrom drift tube. In a time of flight type ion mobility spectrometer, thecross gas flow is used in a manner that is similar to conventional uni-or counter-directional drift gas flow, the drift gas flow does notsubstantially affect the ion separation along the drift axis. Comparedto prior art counter- and uni-direction drift flow design, the crossflow design allows neutral molecule(s) to only travel a short distanceand less time in a drift region. A non-limiting example is shown in FIG.22 where a drift segment is used. However more than one drift segmentcan be used. The drift tube 2201 comprises: an ionization source 2202, adesolvation region 2210 and an analytical segment (drift region) 2205separated by an ion gate 2207. After a sample is introduced into one endof the IMS (in this particular case an ESI source 2202 is used; anyother ionization source could be used), the ionized sample and solventions are formed in the desolvation region 2210, a narrow pulse on theion gate 2207 introduces the ion mixture into the separation segment2205. This configuration has the drift gas flow 2215 (comprised of driftflow for desolvation 2219 and separation 2217) in a direction that issubstantially perpendicular to the drift axis of the ions; the driftaxis generally represent the averaged ion path in the drift tube. Withcross flow configuration, neutral molecules that travel with the driftand desolvation gas flow are not mixed across desolvation and driftregion. Neutral fragments that are generated during drift anddesolvation process in the drift tube are effectively removed from thedrift tube avoiding further gas phase ion molecular interaction in thedrift tube. The cross-directional drift gas can be in a direction thatis between greater than 0° to less than 180° to that of the drift axisof the ions. The cross-directional drift gas is applied to a substantialportion of the desolvation and/or drift region. In many cases thecross-directional drift gas is applied over the entire drift axis. Inaddition, the cross-directional gas flow 2215 can be a drift medium thatcomprises various components. The components may be a plurality chemicalmodifiers and/or a plurality of drift gases. The cross-directional flowcan comprise different drift medium in the different segments and/orregions of the IMS. For example, as shown in FIG. 22, drift gas flow2219 can comprise the same and/or different drift medium as drift gasflow 2217.

In various embodiments, the cross flow configuration for the IMS can becombined with counter or uni-direction flow configurations. For example,if the drift region has a cross flow arrangement as shown in FIG. 22, aportion the drift flow could be exhausted into the desolvation regionand then pumped away from the end of the desolvation region, given thedesolvation region is using a counter direction gas flow arrangement.

In another aspect of the present invention a multiple segmented IMSapparatus is used for pre-separation of the sample. A non-limitingexample is shown in FIG. 23 where two drift segments are used. Howevermore than two drift segment can be used. The drift tube 2301 comprises:a pre-separation segment 2303 and an analytical segment 2305 separatedby an ion gate 2307. The pre-separation segment 2303 resembles thepre-separation column used in chromatography. After a sample isintroduced into one end of the IMS (in this particular case an ESIsource is used, any other ionization source could be used), the ionizedsample and solvent ions are formed in the desolvation region 2310, anarrow pulse on the first ion gate 2312 introduces the ion mixture intothe pre-separation segment 2303. The second ion gate 2307 is timed toopen so that only components of the sample are allowed to enter theanalytical segment 2305. Elimination of the solvent avoids ion-moleculereactions in the analytical segment 2305 of the drift tube 2301.

In various embodiments the two gate IMS apparatus and method, the firstgate transmits packets of ions and these ions move to the second gate.Part of the ions from the first gate will be transmitted through to thesecond gate and the transmitted ions will be further separated throughthe drift region. Ions at the second gate have low density and the spacecharge effect can be reduced and the IMS will have enhanced separation.The IMS separated ions can be detected by a faraday plate and can betransported to a mass analyzer for further analysis.

In another embodiment of the two gate IMS apparatus and method, thefirst gate transmits narrow ion packets. Higher ion mobility ions take ashorter time to get to the second gate than lower mobility ions. Bycontrolling the second gate timing, certain mobility ions aretransmitted through the second gate. The first gate can be controlled totransmit the second, third, fourth, etc. ion packet before the firstpacket reaches the detector. The first and second gate will be operatedsynchronously with different start-on time and width of opening. Ionstransmitted through the second gate will be separated while travelingthrough the drift region and being detected by the detector or beingtransported to the mass analyzer. The first gate opening will have aspecific period which was determined not to mix ions of differentpackets. A grid in front of the detector can be replaced by an exit gateto further limit the ions with specific ion mobility.

A segmented drift tube with multiple ion gates can be used with crossflow design for easy application of different drift media in differentsegments, however, segmented drift tube design could be used with onedrift media, and/or with conventional uni- or counter-direction driftgas flow designs.

In another aspect of the present invention a multiple segmented planarIMS apparatus combined with a cross flow can be used to enhanceseparation of components of a sample. In this case, solvent ions as wellas solvent neutrals are eliminated from the analytical segment. Anon-limiting example is shown in FIG. 24 where two drift segments areused. However more than one drift segment can be used. The drift tube2401 comprises: a pre-separation segment 2403 and an analytical segment2405 separated by an ion gate 2407. The pre-separation segment 2403resembles the pre-separation column used in chromatography. After asample is introduced into one end of the IMS (in this particular case anESI source is used, any other ionization source could be used), theionized sample and solvent ions are formed in the desolvation region2410, a narrow pulse on the first ion gate 2412 introduces the ionmixture into the pre-separation segment 2403. The second ion gate 2407is timed to open so that only components of the sample are allowed toenter the analytical segment 2405. Elimination of the solvent avoidsion-molecule reactions in the analytical segment 2405 of the drift tube2401. This configuration has the drift gas flow 2415 in a direction thatis substantially perpendicular to the drift axis of the ions, the driftaxis generally represent the averaged ion path in the drift tube. Withcross flow configuration, neutral molecules that travel with the driftand desolvation gas flow are not mixed across desolvation and driftregion. Neutral fragments that are generated during drift anddesolvation process in the drift tube are effectively removed from thedrift tube avoiding further gas phase ion molecular interaction in thedrift tube. The cross-directional drift gas can be in a direction thatis between greater than 0° to less than 180° to that of the drift axisof the ions. The cross-directional gas flow can be a drift medium thatcomprises various components. The components may be a plurality chemicalmodifiers and/or a plurality of drift gases. The cross-directional flowcan comprise different drift medium in the different segments of theIMS. For example, as shown in FIG. 24, drift gas flow 2419 can comprisethe same and/or different drift medium as drift gas flow 2417.

A separation apparatus, comprising: an ionization source ionizing asample that contain a least one component in front of an ion gate; adrift tube that has a drift axis along which ions are separated; and adrift flow in a direction that is greater than zero but less than onehundred and eighty degrees from the drift axis. The apparatus canfurther comprise at least one chemical modifier that is added to thedrift flow for separation enhancement. In one embodiment, a separationapparatus comprising: an ionization source ionizing a sample thationizes samples; a drift tube has a drift axis along which ions areseparated, wherein the drift tube has greater than or equal to, twodrift segments in which the ions are separated, and a ion gate that isplaced between drift segments. The separation apparatus may furthercomprises at least one chemical modifier that is added to the driftflow.

In another embodiment of the present invention, a chemical modifier canbe added to different segments or regions of the IMS in order to targetspecific interactions with various components of the sample. Two or moresegments can be used, but for simplification a two segment design willbe discussed. Therefore two or more different chemical modifiers can beused in the IMS without substantially interfering with each other. 0 to100% of modifier can be used in each of the different segments orregions of the IMS. The cross flow drift design is one way to add themodifier, but it is not necessary to use cross flow in order to add themodifiers to each segment or region in the IMS. The different segmentsor regions can be isolated from each other by a number of ways whichinclude but are not limited to; using gates in between or a smallopening, slits or pinholes. In this configuration, a modifier thattargets one functional group can be added to the first region of the IMSand a second type of modifier can be added to the next region thatinteracts with a different functional group. Unlike previous methodswhere a transforming agent, immobilizing agent, or chiral molecule isadded to the sample components prior to ionization, in this process, thesample components are modified in the drift tube in discrete sectionsaccording to the desired interaction. For example, in order to separatea pair of enantiomers in a sample, a chiral modifier added to the crossflow drift gas in the first region of the drift tube which formsdiastereomer components that are then interacted by a second modifieradded to the cross flow drift gas in a second region of the drift tubeto enhance separation.

FIG. 25 shows an IMS where the sample is ionized in the desolvationregion 2510. The drift tube 2501 consists of two regions 2503 and 2505that have an applied electric field (not shown) and are separated by agate 2507. Another gate separates the desolvation region 2510 from thedrift tube 2501 with a gate 2512. In the case of a sample that has twoenantiomer components, this enantiomer pair is ionized in thedesolvation region 2510 and is then allowed to travel into the firstseparation region 2503 whereby 0-100% of a chiral modifier is added tothe cross drift flow 2513 which interacts with the enantiomer pair.Diastereomers are then formed and are let into the second separationregion 2505. These diastereomers are then separated in the secondseparation region with enhanced separation by using 0-100% of a modifierthat is added to the cross drift flow 2517.

One embodiment of this invention is to rigidify the molecules (limit thenumber of conformations) by adding an immobilizing agent to the firstdrift region of the drift tube. The immobilizing agent stabilizes thegas phase structure of analytes in order to enhance the interaction ofthe modifier in the second region of the drift tube in order to enhanceseparation. In variety of embodiments, a modifier that can frame (affix)the higher order structure of a gas phase analyte molecule is used toachieve well-defined gas phase mobility of the analytes. Formingcomplexes with metals and/or other molecules is a non-limiting exampleof this method. Another embodiment of this invention is to add at leastone transforming agent as a modifier to the first drift region, whichbonds/binds (interacts) to at least one component of the sample. Thebonding interactions or attraction forces may include; hydrogen bonds,van der Waals forces, dipole-dipole, steric hindering effects,coordinate covalent bond, metallic bond, ionic bond, non-covalent bond,covalent bond, weak covalent nature, antibonding, short-livedmetastable, clusters, but is not limited to only these. A secondchemical modifier is added to the second region of the drift tube thatinteracts selectively with the component of the sample and/ortransforming agent which resolves/separates the component from othercomponents of the sample based on their measured ion mobilitycharacteristics.

When using a modifier, the modifier can interact with solvent ions andfor additional ions; the modified solvent ions can overwhelm the signalfrom the ions of interest. By using an AC gate, this invention allowsthe removal of the solvent ions before the drift tube separation regionwhere the modifier is introduced to. A non-limiting example is shown inFIG. 26 where a drift segment is used. However more than one driftsegment can be used. The drift tube 2601 comprises: an ionization source2602, a desolvation region 2610 and an analytical segment (drift region)2605 separated by an AC ion gate 2607. After a sample is introduced intoone end of the IMS (in this particular case an ESI source 2602 is used;any other ionization source could be used), the ionized sample andsolvent ions are formed in the desolvation region 2610. The AC gate 2607is operated to reject the low molecular weight solvent ions, and a pulseon the AC ion gate introduces the rest of the ion mixture into theseparation segment 2605. This configuration has the drift gas flow 2615(comprised of drift flow for desolvation 2619 and separation 2617) in adirection that is substantially perpendicular to the drift axis of theions; the drift axis generally represents the averaged ion path in thedrift tube. The cross-directional drift gas can be in a direction thatis between greater than 0° to less than 180° to that of the drift axisof the ions. The cross-directional drift gas is applied to a substantialportion of the desolvation and/or drift region. In many cases thecross-directional drift gas is applied over the entire drift axis. Inaddition, the cross-directional gas flow 2615 can be a drift medium thatcomprises various components. The components may be a plurality chemicalmodifiers and/or a plurality of drift gases. The cross-directional flowcan comprise different drift medium in the different segments and/orregions of the IMS. For example, as shown in FIG. 26, drift gas flow2619 can comprise the same and/or different drift medium as drift gasflow 2617.

In another embodiment, the AC ion gate 2607 is operated as FAIMS (DMS)device, for example, using elongated gate elements as shown in FIG. 18and applying a waveform such as the example shown in FIG. 21. In thisembodiment, a pulse of ions that are characterized by a single FAIMScompensation voltage are allowed through the AC gate; these ions arethen separated in the drift region 2605. This configuration has thedrift gas flow 2615 (comprised of drift flow for desolvation 2619 andseparation 2617) in a direction that is substantially perpendicular tothe drift axis of the ions; the cross-directional drift gas can be in adirection that is between greater than 0° to less than 180° to that ofthe drift axis of the ions. The cross-directional drift gas is appliedto a substantial portion of the desolvation and/or drift region, or overthe entire drift axis. In addition, the cross-directional gas flow 2615can be a drift medium that comprises various components. The componentsmay be a plurality chemical modifiers and/or a plurality of drift gases.The cross-directional flow can comprise different drift medium in thedifferent segments and/or regions of the IMS. For example, as shown inFIG. 26, drift gas flow 2619 can comprise the same and/or differentdrift medium as drift gas flow 2617.

An ion mobility spectrometer apparatus can have an ionization sourcethat is in fluid communication with a drift tube; an AC ion gate thatlocated between the ionization source and the drift tube pulses a groupof ions into the drift tube where the group of ions are separated alonga drift axis, and at least one drift gas that flows substantially in adirection that is greater than zero but less than one hundred and eightydegrees from the drift axis. The group of ions are pre-separated by anAC ion gate comprising applying at least one AC voltage to at least oneof the grid elements of the AC ion gate to pass a pulse of selected ionsinto the drift tube. The AC voltage has an asymmetric waveform as usedin an DMS. the drift gas can also use different drift gases or by addingchemicals into the drift gas. The drift tube is a segmented drift tube.The group of ions are pre-separated by a previous section of a segmenteddrift tube. The segmented drift tube is divided by the AC gatespositioned between each segments only allowing selected ions to pass theion gates. The segment of the drift tube uses different gascompositions. The group of the ions is a mixture of solvent(s) andsample(s). The pre-separation is to eliminate solvent ions for the groupof ions.

An ion mobility spectrometer method can be operated by forming ions inan ionization source that is in fluid communication with a drift tube;pulsing a group ions that into a drift tube; separating the group ofions along a drift axis of the drift tube, and; providing at least onedrift gas that flows substantially in a direction that is greater thanzero but less then one hundred and eighty degrees from the drift axis.The group of ions are pre-separated by an AC ion gate comprisingapplying at least one AC voltage to at least one of the grid elements ofthe AC ion gate to pass a pulse of selected ions into the drift tube.The AC voltage has an asymmetric waveform as used in an DMS. The driftgas further comprises adding chemicals into the drift gas. The drifttube is a segmented drift tube. The group of ions are pre-separated by aprevious section of a segmented drift tube. The segmented drift tube aredivided by the AC gates positioned between each segments only allowingselected ions to the ion gates. Each segment of the drift tube usesdifferent gas compositions. The group of the ions is a mixture ofsolvent(s) and sample(s). The pre-separation is to eliminate solventions.

A separation method, comprising ionizing a sample with at least onecomponent; separating the ionized sample along a drift axis of a drifttube, and proving a drift flow in a direction that is greater than zerobut less than one hundred and eighty degrees from the drift axis. Theseparation method may further comprise removing neutral molecules in thedrift tube along with the drift flow; the neutral molecules could be,but not limited to, one component of the sample; fragment of a samplemolecule; contaminants in the apparatus. In one embodiment, a separationmethod comprising: ionizing a sample with at least one component;providing the sample to an ion mobility based spectrometer with greaterthan or equal to, two drift segments separated by an ion gate betweenthe drift segments; transporting the ionized sample as a ion packetalong a drift axis; and pre-separating the ion packet in one of thedrift segments prior to further separation in other separation segments.This separation method may further comprises; adding at least onechemical modifier to a drift gas flow that is in a direction to that ofthe drift axis of the ions that is between greater than 0 degrees toless than 180 degrees.

In various embodiments, the drift gas can be supplied to the higherdimension in the direction that is in substantially parallel to thelower dimension. Under linear flow conditions and the parallel flowpattern, for example, limited mixing of drift gas near the dimensioninterface is expected.

In SBA mode operation, the sample is provided into the spectrometerthrough an inlet port. Through the ionization source, the ionized thesamples are brought into the first dimension drift region by gas flow.In various embodiments of the SBA operational mode, the first dimensiondrift tube can be used as ion storage device to, e.g., increase the dutycycle of the device.

In various embodiments of Continuous First Dimension Ionization (CFDI)mode operation, the samples are introduced to the spectrometer as pulsesof gas. The sample gas pulse can be formed in a wide variety of ways,for example, by thermally desorbing chemicals from a surface, as theeluent of a chromatographic separation, by pumping the sample into thespectrometer for a short period of time, introduction through a pulsedvalve, etc. In many embodiments, the flow under a linear flow condition,and a “plug” of gas phase sample is directed from the inlet port towardsthe ionization source by gas flow. Pulses of reactant ions (preferablyat high density) are generated by the ionization source and guided bythe electrical drift field to drift towards the sample “plug”. As thepulse of reactant ions and samples intercept in the first dimension, aportion of the samples are ionized. As the sample encounters multiplereactant ion pulses in the same acquisition period, chemicals in thesample “plug” are ionized. Chemicals with different properties (e.g.,charge affinity) can thus be separated and detected at differentlocations on the detector matrix. This gas phase titration method canimprove ionization efficiency of ion mixture where chemicals withdifferent properties coexist. By this means chemicals that can not bedetected in conventional IMS can be detected.

In various embodiments, the CFDI can also be performed in the reactionregion. A plurality of pulses of reactant ion is generated by pulsingthe ion gate while pulsed samples are introduced to the spectrometerfrom a gas port. In this implementation, the ion ion gate is removed orkept open. Pulse of ions generated in the reaction region are separatedin the first dimension drift region, and then the separated ions areextracted in a higher dimension drift region for further ion mobilityanalysis if so desired. In various embodiments, the CFDI method can beused as an independent ionization source directly interfaced tospectrometers, such as a differential mobility spectrometer, ionmobility spectrometer or a mass spectrometer, either inline orperpendicular to the direction of the drift electric field. Inembodiments where CFDI is used for a single IMS, a shutter grid will beused. The ionized chemical species continue to drift in the drift regionafter formation in the reaction region. Similarly, interfaces to otherspectrometers, such as differential ion mobility spectrometers and massspectrometers, can also be realized by placing the sample inlet of theseinstruments directly after the reaction region.

The CFDI mode can be performed using reactant ions with differentchemical properties. For example, modifying the ion chemistry using avariety of chemical reagents that react with initial reactant ions cangenerates reactant ions with different chemical properties. These ionicspecies can be used, e.g., to ionize samples introduced to thespectrometer. Similar effects can be achieved, e.g., by using anionization source that can generate different ionic species or chargedparticles/droplets. In various embodiments, altering the ionizationchemistry can be used to achieve substantially selective ionization oftargeted chemicals in the sample. For example, a series of ion pulsewith different chemical properties can be used to ionize chemicals withcompatible ionization properties in the sample.

In Selective Ion Introduction (SII) mode operation, one or multiplegroups of selected ions are kicked out into a higher dimension. Theselective kick out can be realized by applying a kick out voltage at apredetermined time to the region where ions of interests are travelingthrough at a given timing. In various embodiments, the kick out pulse isnot necessarily applied to a selected region of the lower dimension, butthe higher dimension drift chamber does not intercept the lowerdimension only over a portion of length of the lower dimension; thus,e.g., a selected location can be designed only to allow a small group ofions to be kick out into the second dimension. A similar result asdescribed with respect to MSS mode can be achieved by controlling thekick out timing and performing multiple acquisition cycles.

In various embodiments of MDIMS systems, the higher dimension driftregion, such as the second dimension region, can be operated indifferent phases of drift media, e.g. gas or liquid. The liquid phasedrift cell can be constructed with two parallel plates or grids insteadof a conventional drift tube design. The liquid phase drift cell can bea thin layer of liquid that has an electric field across the layer. Thehigher order dimension drift cell has drift axis that is substantiallyparallel or substantially perpendicular to the first dimension driftaxis. The higher dimension drift cell has multiple compartments(channels) that are substantially perpendicular to the lower dimensiondrift axis. The higher dimension drift cell can be used for selectivelycollecting samples separated in the lower dimension drift tube. Thehigher dimension drift cell can be further interface to other separationand detection apparatus, including but not limited to electrophoresis,chromatography, UV absorption and other spectroscopic apparatus.

In various embodiments of MDIMS systems of the present inventions,different drift gases are used in different drift tubes and/ordimensions of the MDIMS to separate ionic species in a higher dimension(e.g., a second dimension) that are not sufficiently separated in thedrift gas in a lower dimension (e.g., the first dimension). It is to beunderstood that the drift gas can be a mixture of two or more gases.Similar separations can also be done by varying other drift chamberconditions.

Various embodiments that can be used to realize the SII mode operationwith IMS^(n). By reducing the physical size of the higher dimensions andcontrolling the timing of the kick out pulse, a selected group of ionsthat drifted into the kick out region can be brought into a higherdimension drift chamber where they can be further separated. The sameprocess can be continued until the nth separation performed in differentdrift chambers. The geometry of the interconnected drift chambers can betwo dimensional or three dimensional, thus the number of times a higherorder mobility separation can be conducted is not necessarily limited bythe physical space available for the spectrometer.

In various embodiments, a three dimensional MDIMS can be used for SIImode operation. When gas phase sample is introduced into the reactionregion of the first dimension drift tube, between two ion gates, thesample is ionized by either CFDI or conventional ionization methods withreactant ions created by the ionization source. The sample ions mixedwith reactant ions are pulsed into the first drift region. Under theguidance of the electric field generated by ion guide, the ion mixtureseparates in the first dimension. At a predetermined timing when ions ofinterest drift into the kick out region, a kick out voltage can beapplied to a set of electrodes (including a split ion guide and grids)to extract ions into the second dimension. As ions are compressed in theinterface between the kick out region and a second dimension driftregion, narrow pulses of plural separated ions are created at thebeginning of the second dimension drift region. The ions pulses areseparated in the drift region that is guarded by ion guides. The furtherseparated ions are extracted from second ion kick out region into thethird drift chamber that has a drift direction that is orthogonal to thefirst and second dimension. The extracted ions repeat the processdescribed above in the third dimension or higher.

In various embodiments, a MDIMS can operate in SII mode with a twodimensional structure. One peak that is isolated by the first dimensiondrift tube is extracted into second dimension, and then one peakisolated by the second dimension drift tube is extracted into the thirddimension having a drift direction that is substantially perpendicularto the second dimension and substantially anti-parallel to the firstdimension. In this example, the drift axes of all dimensions are on thesame plane.

For example, in various embodiments, this configuration can beinterfaced to other detectors, such as a mass spectrometer. IMS-MSsystems are commonly used to achieve mobility based separation beforemass analysis. The interface to a mass spectrometer can be in-line withion drifting direction behind the detector matrix. An interface to amass spectrometer can be through an opening on the second dimensiondetector matrix, or perpendicular to the drifting direction using a kickout pulse to push ions into the interface. Higher ion transportationefficiency is expected in the latter case.

In various embodiments of the MDIMS, a compact MDIMS device can beconfigured with three dimensions, including one first dimension chamber,two second dimension drift chambers, and two third dimension chambers,with a largest dimension of <10 cm. The configuration is to realize bothCFDI and DPIE with SII mode. In CFDI operation, the reactant ions areformed in ion source and pulsed into the reaction region to selectivelyionize the pulsed sample. Ionized samples are separated in the firstdimension drift region and then further separated in a higher dimensiondrift region.

In DPIE operation, both positive and negative ions formed in theionization source and reaction region are carried into the firstdimension by carrier flow without effluence of the electric field. Thepositive and negative ions are extracted in to the second dimensiondrift chambers. The sample ions are detected on the detector matrix inthe first dimension, second dimension or third dimension depending onthe instrument usage and it is software controlled. For fast screeningoperation, ions are detected at lower dimension detectors for highthroughput. For highest resolution, ions are measured at the thirddimension detectors. The practical unit includes a sample inlet, asample inlet control valve, an ionization source, and a first dimensiondrift region. The drift flow is designed to sweep cross the second driftregion and third drift region. At the drift gas inlet, a flowdistribution system is used to assure even drift flow across the entiredrift chambers.

A portable system package can include a pneumatic system, electronicsand computer controls, a user interface and display, battery power, anda MDIMS.

A modularized design approach is preferably used in the MDIMS of thepresent inventions to facilitate the provision of future upgrades. Forexample, a different ionization source may be desired for differentapplications. Such sources may be, e.g., a corona discharge,electrospray ionization or desorption electrospray ionization. Theprovision of a modular design can facilitate the changing of the ionsource.

In another aspect, the functionality of one or more of the methodsdescribed above may be implemented as computer-readable instructions ona general purpose processor or computer. The computer may be separatefrom, detachable from, or may be integrated into a MDIMS system. Thecomputer-readable instructions may be written in any one of a number ofhigh-level languages, such as, for example, FORTRAN, PASCAL, C, C++, orBASIC. Further, the computer-readable instructions may be written in ascript, macro, or functionality embedded in commercially availablesoftware, such as EXCEL or VISUAL BASIC. Additionally, thecomputer-readable instructions could be implemented in an assemblylanguage directed to a microprocessor resident on a computer. Forexample, the computer-readable instructions could be implemented inIntel 80×86 assembly language, if it were configured to run on an IBM PCor PC clone. In one embodiment, the computer-readable instructions canbe embedded on an article of manufacture including, but not limited to,a computer-readable program medium such as, for example, a floppy disk,a hard disk, an optical disk, a magnetic tape, a PROM, an EPROM, orCD-ROM (or any other type of data storage medium).

All literature and similar material cited in this application,including, but not limited to, patents, patent applications, articles,books, treatises, and web pages, regardless of the format of suchliterature and similar materials, are expressly incorporated byreference in their entirety. In the event that one or more of theincorporated literature and similar materials differs from orcontradicts this application, including but not limited to definedterms, term usage, described techniques, or the like, this applicationcontrols.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described inany way.

The claims should not be read as limited to the described order orelements unless stated to that effect. While the present inventions havebeen described in conjunction with various embodiments and examples, itis not intended that the present inventions be limited to suchembodiments or examples. On the contrary, the present inventionsencompass various alternatives, modifications, and equivalents, as willbe appreciated by those of skill in the art.

It is recognized that modifications and variations of the inventiondisclosed herein will be apparent to those of ordinary skill in the artand it is intended that all such modifications and variations beincluded with the scope of the appended claims.

What is claimed is:
 1. An ion mobility analyzer apparatus comprising: a.A first ion gate that is located between an ionization source and afirst drift region of a drift tube, and pulses a group of ions into thefirst drift region where the group of ions are separated along a driftaxis of the first drift region; b. A second ion gate that is an AC iongate located between the first drift region of the drift tube and asecond drift region of the drift tube, and pulses a group of ions intothe second drift region where the group of ions are separated along adrift axis of the second drift region; wherein i. the AC ion gatecomprises at least one pair of adjacent grid elements that can be set atthe same or different potentials; and ii. at least one AC power supplyapplies at least one AC voltage to the grid elements to pass a pulse ofselected ions into the spectrometer; wherein the pulse of selected ionsis generated by applying a first frequency and a first amplitude of theAC voltage to at least one of the grid elements for a period time andsubsequently applying a second frequency and/or a second amplitude ofthe AC voltage to at least one of the grid elements; and c. At least onedrift gas in the drift tube.
 2. The apparatus of claim 1, wherein atleast one power supply applies at least one AC voltage to at least onegrid element of the AC ion gate.
 3. The apparatus of claim 2, whereinthe at least one power supply alters the AC waveform, frequency and/oramplitude of the AC voltage.
 4. The apparatus of claim 1, wherein thefirst ion gate is a first AC ion gate, wherein a. the AC ion gatecomprises at least one pair of adjacent grid elements that can be set atthe same or different potentials; and b. at least one AC power supplyapplies at least one AC voltage to the grid elements to pass a pulse ofselected ions into the spectrometer; wherein the pulse of selected ionsis generated by applying a first frequency and a first amplitude of theAC voltage to at least one of the grid elements for a period time andsubsequently applying a second frequency and/or a second amplitude ofthe AC voltage to at least one of the grid elements.
 5. The apparatus ofclaim 4, wherein a first power supply supplies a first AC voltage to thefirst AC ion gate, and the same power supply or a different power supplysupplies a second AC voltage to the second AC ion gate, wherein thefirst AC voltage has an AC waveform, frequency, and/or amplitude that isdifferent from that supplied to the second AC ion gate.
 6. The apparatusof claim 1, wherein the drift tube has gas ports that direct the driftgas flow in uni-, counter-, or cross-flow direction.
 7. An ion mobilityanalyzer method comprising: a. Pulsing a group of ions into a firstdrift region of the drift tube using a first ion gate; b. Separating thegroup of ions along a drift axis of the first drift region; c. Pulsingat least one group of ions into a second drift region of the drift tubethrough a second ion gate that is an AC ion gate; wherein a pulse ofselected ions is generated by applying a first frequency and a firstamplitude of an AC voltage to at least one of the grid elements for aperiod time and subsequently applying a second frequency and/or a secondamplitude of the AC voltage to at least one of the grid elements; d.Separating the at least one group of ions along a drift axis of thesecond drift region; and e. Providing at least one drift gas in thedrift tube.
 8. The method of claim 7, wherein at least one power supplyapplies at least one AC voltage to at least one grid element of the ACion gate.
 9. The method of claim 8, wherein controlling the power supplyby altering the AC waveform, frequency and/or amplitude.
 10. The methodof claim 7, wherein operating the first ion gate as an AC ion gate bygenerating a pulse of selected ions by applying a first frequency and afirst amplitude of an AC voltage to at least one of the grid elementsfor a period time and subsequently applying a second frequency and/or asecond amplitude of the AC voltage to at least one of the grid elements.11. The method of claim 7, wherein operating the ion gates to block orallow through a group or multiple groups of ions at the first AC iongate, and to block or allow through a different group or multiple groupsof ions at the second AC ion gate by controlling a first power supply tosupply a first AC voltage with a first AC waveform, frequency andamplitude to the first AC ion gate and controlling the first powersupply or a second power supply to supply an AC voltage with a differentAC waveform, frequency and/or amplitude to the second AC ion gate. 12.The method of claim 11, wherein changing the output of the power supplyto alter the AC waveform, frequency and/or amplitude supplied to thesecond AC ion gate to a different waveform, frequency and/or amplitudewhen targeted ions arrive at the second AC ion gate.
 13. The method ofclaim 12, wherein allowing ions to pass through the second AC ion gatewhen targeted ions arrive at the second AC ion gate.
 14. The method ofclaim 7, wherein directing the drift gas in uni-, counter, or cross-flowdirection.
 15. An ion mobility analyzer method comprising: a. Pulsing agroup of ions into a first drift region of the drift tube using a firstion gate; b. Separating the group of ions along a drift axis of thefirst drift region; c. Selectively passing at least one group of ionsinto a second drift region of the drift tube through a second ion gatethat is an AC ion gate by applying a series of AC voltages in a certainsequence during ion mobility measurement; d. Separating the group ofions along a drift axis of the second drift region; and e. Providing atleast one drift gas in the drift tube.
 16. The method of claim 15,wherein selectively passing at least one group of ions into the seconddrift region by controlling a power supply to apply at least one ACvoltage to the second AC ion gate at a given timing.
 17. The method ofclaim 15, wherein operating the first ion gate as an AC ion gate bygenerating a pulse of selected ions by applying a first frequency and afirst amplitude of an AC voltage to at least one of the grid elementsfor a period time and subsequently applying a second frequency and/or asecond amplitude of the AC voltage to at least one of the grid elements.18. The method of claim 15, wherein operating the ion gates to block orallow through a group or multiple groups of ions at the first AC iongate, and to block or allow through a different group or multiple groupsof ions at the second AC ion gate by controlling a first power supply tosupply a first AC voltage with a first AC waveform, frequency andamplitude to the first AC ion gate and controlling the first powersupply or a second power supply to supply an AC voltage with a differentAC waveform, frequency and/or amplitude to the second AC ion gate.